Lisdexamfetamine dimesylate is approved and marketed in the United States for the treatment of attention-deficit hyperactivity disorder in pediatric patients. The active compound lisdexamfetamine contains D-amphetamine covalently linked to the essential amino acid L-lysine. Controlled release of D-amphetamine, a psychostimulant, occurs following administration of lisdexamfetamine to a patient. The controlled release has been reported to occur through hydrolysis of the amide bond linking D-amphetamine and L-lysine.
A procedure for making lisdexamfetamine hydrochloride is described in U.S. Pat. No. 7,223,735 to Mickle et al. (hereinafter Mickle). The procedure involves reacting D-amphetamine with (S)-2,5-dioxopyrrolidin-1-yl 2,6-bis(tert-butoxycarbonylamino)hexanoate to form a lysine amphetamine bearing tert-butylcarbamate protecting groups. This intermediate is treated with hydrochloric acid to remove the tert-butylcarbamate groups and provide lisdexamfetamine as its hydrochloride salt. In a subsequent publication, U.S. Pat. No. 7,655,630 Mickle et al. describe the conversion of the lysine amphetamine bearing tert-butylcarbamate protecting groups to the final dimesylate salt by treatment with methanesulfonic acid. A different procedure to link D-amphetamine to the 2,6-bis(tert-butoxycarbonylamino)hexanoate is described in U.S. Pat application No 2011/0196173 A1 to Meudt et al. (hereinafter Meudt). The procedure involves reacting D-amphetamine with 2,6-bis(tert-butoxycarbonylamino)hexanoic acid in the presence of an alkylphosphonic anhydride to form a lysine amphetamine bearing tert-butylcarbamate protecting groups and cleaving the protecting groups in a one-pot reaction or in two or more separate steps.
Another procedure for converting amphetamine enriched in the dextro-enantiomer (at least 90%) is described in US 2012/0157706 A1 to Bauer et al., (hereinafter Bauer). The procedure involves reacting amphetamine having an enantiomeric ratio of less than 99:1 (D-amphetamine to L-amphetamine) with (S)-2,5-dioxopyrrolidin-1-yl 2,6-bis(benzyloxycarbonylamino)hexanoate to form a lysine amphetamine bearing benzylcarbamate protecting groups. The lysine amphetamine bearing benzylcarbamate protecting groups is further purified by crystallizing from a mixture comprising (i) at least one of a C1-C4 aliphatic alcohol, C1-C4 aliphatic carboxylic acid, aliphatic tertiary amine, or water, and (ii) (C1-C4 alkyl)-CO2(C1-C4 alkyl), to provide the lysine-amphetamine compound in up to purity of at least 99.95% (w/w), when starting with a mixture of D-amphetamine and L-amphetamine having an enantiomeric ratio of less than 99:1 (D-amphetamine to L-amphetamine). The purified lysine amphetamine bearing benzylcarbamate protecting groups is converted to lisdexamfetamine dimesylate by catalytic hydrogenation to remove the benzyloxy protecting groups and subsequent addition of methanesulfonic acid to generate the final product.
The routes described above for the preparation of lisdexamfetamine start from enantiomerically pure D-amphetamine or D-amphetamine which is enriched to at least 90:10 (D-amphetamine to L-amphetamine). D-amphetamine is in turn prepared from racemic amphetamine by enantiomeric resolution of a diastereomeric salt using a chiral acid (e.g. tartaric acid) or by a multi-step synthesis from expensive raw materials 1R,2S-(−)-norephedrine or 1R,2S-(+)-norpseudoephedrine. A procedure for making D-amphetamine from either 1R,2S-(−)-norephedrine or 1R,2S-(+)-norpseudoephedrine is described in U.S. Pat. No. 6,399,828 to Boswell and Lo (hereinafter Boswell). The procedure involves converting the 1R,2S-(−)-norephedrine or 1R,2S-(+)-norpseudoephedrine to the corresponding 0-acetyl-phenylpropanolamine salt, followed by catalytic hydrogenation to D-amphetamine salt. A variation of this procedure is described in U.S. Patent application 2009/0292143 A1 to Buenger et al. (hereinafter Buenger). The procedure involves converting the 1R,2S-(−)-norephedrine or 1R,2S-(+)-norpseudoephedrine to the corresponding 1-chloro-1-phenyl-2-propanolamine salt, treating the 1-chloro-1-phenyl-2-propanolamine salt with activated carbon followed by catalytic hydrogenation to D-amphetamine salt. Yet another variation of this procedure is described in WO 2010/058206 A1 to Fishbein and Mencel (hereinafter Fishbein). The procedure involves converting catalytic hydrogenation of the oxazolidine of 1R,2S-(−)-norephedrine or 1R,2S-(+)-norpseudoephedrine to D-amphetamine.
A hybrid approach to lisdexamfetamine starting from 1R,2S-(−)-norephedrine is described in WO 2010/148305 A1 to Jass et al. (hereinafter Jass). 1R,2S-(−)-norephedrine was first converted to the corresponding 1-chloro compound with thionyl chloride and the resulting chloro-D-amphetamine hydrochloride was coupled with a bis-protected lysine to give a bis-protected chloro-lisdexamfetamine intermediate. The bis-protected chloro-lisdexamfetamine was converted to the corresponding bis-protected lisdexamfetamine by catalytic hydrogenation, and then converted to lisdexamfetamine dimesylate by treatment with methanesulfonic acid.
Furthermore, the coupling of the amphetamine to the protected lysine amino acid derivative for each of these methods requires either an expensive leaving group such as the N-hydroxysuccinimide ester attached to the carboxyl group of the protected lysine amino acid to promote amide coupling conditions or other reagents used to activate a carboxylic acid group for reaction with an amine (e.g., D-amphetamine) include, for example, carbodiimides (such as dicyclohexylcarbodiimide; N,N′-diisopropylcarbodiimide, and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide), phosphonium reagents (such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), uronium reagents (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), anhydrous 1-hydroxybenzotriazole, and phosphonic acid anhydrides (such as propane phosphonic acid anhydride, sold under the tradename T3P®).
A shorter, more cost-effective route would be provided by selective conversion of racemic amphetamine to lisdexamfetamine by taking advantage of the chirality of the protected lysine amino acid derivative. Miyazawa et al., J. Chem Soc. Perkin Trans 1, 2002, 390-395 describe the α-chymotrypsin catalyzed conversion of a racemic amine and N—Z—(S)-phenylalanine esters to give primarily the S,S-diastereomer of the resulting amide. Pera et al., Tetrahedron Letters, Vol 37, 3609-3612 (1996) describe the papain catalyzed conversion of a racemic amino acid ester (Z-γ,γ′-di-tert-butyl-D,L-Carboxyglutamic acid, methylester) with a chiral amino acid to give the diastereomerically pure L-carboxyglutamic acid-containing dipeptide while the D-Carboxyglutamic acid, methylester remained in the solution unreacted.
MUNOZ et al., in Organic and Biomolecular Chemistry, 2011, pp 8171-8177, Vol. 9, nb: 23 describe enzymatic enantiomeric resolution of phenylethylamines (structurally related to amphetamine. However, the resolution described by MUNOZ et al. is directed to compounds which (unlike lisdexamfetamine) contain only a single stereo-center. GONZALEZ-SABIN et al., in Tetrahedron Asymmetry, 2000, pp 1315-1320, Vol. 13 describe CAL-B-catalyzed resolution of β-substituted isopropylamines. However, GONZALEZ-SABIN describe the use of Candida antarctica lipase B for enantioselective acylation of racemic amines, wherein the major enantiomer product is the (R)-amide.
There remains a need for new methods for the preparation of lisdexamfetamine and salts thereof, wherein the lisdexamfetamine is prepared with high enantiomeric/diastereomeric purity. The present invention addresses this need and further, provides one or more additional process advantages, as described in more detail hereinafter.